Peritoneal Dialysis International, Vol. 20, pp. 396–411 Printed in Canada. All rights reserved.
Copyright 2000 International Society for Peritoneal Dialysis ISPD GUIDELINES/RECOMMENDATIONS
William F. Keane,1 George R. Bailie,2 Elizabeth Boeschoten,3 Ram Gokal,4 Thomas A. Golper,5 Clifford J. Holmes,6 Yoshindo Kawaguchi,7 Beth Piraino,8 Miguel Riella,9 Stephen Vas10 Department of Medicine,1 Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota; Albany College of Pharmacy,2 Albany, New York, U.S.A.; Department of Peritoneal Dialysis,3 Academic Medical Center, Amsterdam, The Netherlands; Manchester Royal Infirmary,4 Manchester, United Kingdom; Vanderbilt University Medical Center,5 Nashville, Tennessee; Baxter Healthcare Corporation,6 McGaw Park, Illinois, U.S.A.; Renal Division,7 Jikei-kai University, School of Medicine, Tokyo, Japan; University of Pittsburgh Medical Center,8 Pittsburgh, Pennsylvania, U.S.A.; Renal Division,9 Department of Medicine, Evangelic School of Medicine, Curitiba Parana, Brazil; University of Toronto,10 Toronto Hospital, Toronto, Ontario, Canada Peritonitis is a common clinical problem that occurs coccus peritonitis, the relative incidence of gram- in patients with end-stage renal disease treated by peritoneal dialysis (PD). Although the incidence Many different antimicrobial agents have been of peritonitis varies from center to center, since the used to treat PD peritonitis. As in the past, the cur- 1980s it has progressively declined, and during the rent Committee reviewed experiences reported in the past decade approximately 1 episode every 24 pa- literature and formulated recommendations based tient-treatment-months was routinely observed. In upon these assessments. Over the years, a variety of some centers, 1 episode every 60 patient-treatment- different regimens have been proposed based upon months has been achieved, in large part because of these experiences. Antibiotics have been administered exceptional patient education, as well as new con- intraperitoneally (IP), or intravenously (IV), or orally, nector and catheter technologies. The more recent and a number of different dosing regimens have been introduction of automated peritoneal dialysis (APD) utilized. Unfortunately, no single regimen has been has also contributed to the growth of PD, but this shown in appropriate clinical trials to be most technique is also complicated by episodes of A diagnostic and therapeutic approach to the pa- The development of disconnect systems has had tient with presumptive PD peritonitis was published an important effect on overall reduction of the inci- in 1987 and revised in 1989, 1993, and 1996. These dence of peritonitis episodes, particularly those due latter recommendations contained a number of new to skin organisms. A variety of micro-organisms may recommendations based upon intermittent dosing. In cause PD peritonitis. Gram-positive organisms, par- addition, the recent emergence of vancomycin resis- ticularly Staphylococcus aureus and S. epidermidis, tance has created a therapeutic dilemma of interna- have been the most frequent pathogens. However, in tional proportions (see Recommendations for patients utilizing the disconnect systems, with the Correspondence to: W.F. Keane, Division of Nephrology, reduction in the incidence of gram-positive staphylo- Department of Medicine, Hennepin County Medical Cen- The above-mentioned authors are members of the Ad Hoc ter, 701 Park Avenue South, Minneapolis, MN 55415 U.S.A.
Advisory Committee on Peritonitis Management of the International Society for Peritoneal Dialysis (ISPD).
Received 14 May 2000; accepted 14 May 2000.
Gram stain, immediate therapy is not indicated. Simi- larly, if more than 10% of peritoneal leukocytes are to our recommendations were proposed in 1996. As eosinophils and the Gram stain is negative, immedi- always, individual clinical situations and variability ate antimicrobial therapy is usually unnecessary.
in patient populations may necessitate modification Patients with cloudy fluid accompanied by abdomi- of these recommendations. Importantly, it is recog- nal pain and/or fever require prompt initiation of nized that there are clinical situations in which van- empiric therapy (Table 2). Neither the differential nor comycin is the appropriate antibiotic to be used; the magnitude of the WBC elevation has been shown however, the committee still recommends that rou- to be helpful in predicting the causative organism.
tine and prophylactic use of this antimicrobial agent There is some evidence that peritonitis caused by S. aureus or gram-negative bacilli may be accompa- We do not suggest that the recommendations out- nied by more severe symptoms than an infection lined in this report represent the only acceptable ways caused by coagulase-negative staphylococci. However, to manage PD patients with peritonitis. Nonetheless, altering the empiric therapy based on the severity of the purpose of this document is to present a system- symptoms or the dialysate cell count is not recom- atic approach reflecting a changing microbial envi- mended. A Gram stain is positive in 9% – 40% of peri- ronment and the emergence of new antibiotics.
tonitis episodes and, when positive, is predictive of In addition to these therapeutic recommendations, eventual culture results in approximately 85% of an important clinical management tool has been the cases. A Gram stain is particularly useful in the early development and utilization of techniques in each recognition of fungal peritonitis. Culture of dialysate center for monitoring the incidence of peritonitis, effluent should always be performed prior to initia- exit-site infections (ESI), and tunnel infections in tion of antibiotic therapy, but treatment should not the PD population. This epidemiological approach be delayed while waiting for culture results.
should allow program directors to assess whether a Diagnosis of Peritonitis in APD Patients: Patients change in the frequency and incidence of peritonitis on various forms of APD require a modified approach has occurred in their patient population, and thus to diagnosis and treatment of peritonitis. These pa- to provide an index of quality of care. Attention to tients receive a period of consecutive, relatively short changing microbial biograms within a center is also exchanges during the night (nocturnal exchanges), of major importance in the setting of increasing and may have only a partial exchange or a dry abdo- prevalence of vancomycin-resistant staphylococcus men during the day (daytime exchanges).
and enterococcus organisms. Finally, this year Diagnostic criteria for peritonitis were established 2000 Update is focused on the adult population; based on clinical experience with CAPD patients separate pediatric recommendations will be pub- whose dwell times were 4 – 6 hours in duration. Con- cerns have been raised that the shorter dwell times of APD patients with suspected peritonitis could re- sult in misleadingly low dialysate cell counts and falsely negative cultures. In pediatric patients, 70% of whom are treated with APD, this has not been the Patients: In patients with cloudy fluid and/ case. For more than a decade, CAPD peritonitis diag- or abdominal pain and/or fever, a sample of the ap- nostic and treatment criteria and methods have been propriate (i.e., > 4 hours’ dwell time) dialysate efflu- successfully applied to the management of pediatric ent should be obtained for laboratory evaluation patients receiving APD, with only minor modifications including a cell count with differential, Gram stain, (see Kuizon et al., 1995). The following recommenda- and culture (Table 1). An elevated dialysate count of tions are based on this pediatric experience and may white blood cells (WBC) of more than 100/mm3, of prove useful in the management of adults on APD.
which at least 50% are polymorphonuclear neutro- phils (PMN), is supportive of the diagnosis of micro- bial-induced peritonitis, and calls for immediate Initial Clinical Evaluation of Patient with Suspected initiation of antimicrobial therapy. In asymptomatic patients with only cloudy fluid, it is reasonable to delay initiation of therapy until the results of the cell • Symptoms: cloudy fluid and abdominal pain count, differential, and Gram stain are available, as • Gram stain and culture on initial drainage long as these studies can be performed expeditiously (i.e., within 2 – 3 hours). If there is no increase in the • Choice of final therapy should always be guided by anti- peritoneal WBC count, the differential does not show a predominance of PMN, and no bacteria are seen on Empiric Initial Therapy, for Peritoneal Dialysis-Related Peritonitis, Stratified for Residual Urine Volume Peritonitis diagnosis and treatment data in adults on prompt initiation of antifungal therapy. The finding of gram-positive cocci and gram-negative rods to- Cloudy fluid and abdominal pain remain the hall- gether suggests the possibility of a perforated abdomi- mark of peritonitis in APD-treated patients. Occasion- nal viscous, and prompt surgical evaluation is ally, the initial drain of the “residual” fluid that has been present in the abdomen all day in patients with Unfortunately, on many occasions the Gram stain only partial or dry diurnal exchanges will appear is unavailable, delayed, or negative for any specific cloudy in the absence of peritonitis. The WBC may organisms. Empiric therapy is indicated in these con- exceed 100/mm3, but mononuclear cells predominate ditions (Tables 1 and 2). There are some clinical clues and abdominal pain is not present. More important, that may be helpful. There is a slight statistical likeli- in the absence of infection the initially cloudy dialy- hood that the causative pathogen will be the same as sate rapidly clears with initiation of APD.
the most recent infection. If the exit site is infected If cloudy fluid, and/or abdominal pain, and/or fever with pseudomonas or S. aureus when peritonitis pre- is/are observed at any point in the daily APD treat- sents, there is a high probability that the peritonitis ment cycle, the patient should notify the dialysis cen- is caused by the same organism. If the patient is hav- ter immediately for further specific instructions, ing frequent peritonitis episodes, then relapse or re- including clinical evaluation. A sample of dialysate currence with the same organism is likely.
effluent should be obtained for cell count, differen- It is recognized that many patients treated with tial, Gram stain, and culture, as with CAPD patients.
PD reside in locations that are remote from medical If the fluid is very turbid, the initial sample is suffi- facilities, and thus may not be seen expeditiously fol- cient for study, regardless of the length of the dwell lowing the onset of symptoms. In addition, these PD time that produced it. In equivocal cases, or in pa- patients may not have immediately available micro- tients with systemic or abdominal symptoms in whom bial and laboratory diagnostic services. Since most dialysate appears to be clear, a second exchange is experts agree that prompt initiation of therapy for performed with a dwell time of at least 2 hours. Obvi- peritonitis is critical, it is necessary that the patient ously, clinical judgment should guide initiation of report symptomatology to the center immediately.
therapy. Using this technique, the incidence of cul- Prompt initiation of therapy by these patients remote ture-negative peritonitis has remained approximately from the center is of obvious importance and requires 20%, similar to that reported in CAPD patients.
the availability of antimicrobials in the patient’s home.
Clinical Utility of the Gram Stain: If, on initial This approach has been broadly accepted by medical evaluation, the Gram stain reveals a gram-positive care providers worldwide and has demonstrated effi- organism, therapy with a single antibiotic with activ- cacy. Instructions for the reporting of symptomatol- ity against gram-positive organisms should be initi- ogy and the utilization of home antimicrobial therapy ated. However, identification of a single species by should be considered part of PD patient training.
Gram stain does not preclude the presence of other species present in lesser concentrations. Thus, the Gram stain results must be considered preliminary.
In rare cases, the Gram stain may indicate gram-nega- tive organisms, and the selection of an antimicrobial vancomycin-resistant micro-organisms has been agent with activity against gram-negative bacteria noted. Initially, vancomycin resistance was confined is appropriate. The Gram stain may also be useful in to enterococci isolated from patients who were criti- revealing the presence of yeast, and thus allow for cally ill in intensive care units. It has subsequently which is an independent predictor of patient survival.
There is good evidence showing a more rapid loss of residual renal function in patients receiving aminoglycosides, even for short periods. First-genera- tion cephalosporins do not adequately cover MRSA.
Alternatives to ceftazidime (in patients with a re- sidual urine volume of < 100 mL/day) may be cefazolin or cephalothin in combination with an aminoglycoside, or clindamycin, or vancomycin in that order of pref- This strategy is consistent with the desire to pre- agents that could be used have not been proven in serve vancomycin for true methicillin-resistant organ- therapeutic trials. This change in vancomycin sensi- isms. Ceftazidime was selected as empiric therapy tivity has prompted a number of worldwide agencies because of its activity against both gram-positive and to discourage routine use of vancomycin for prophy- laxis, for empiric therapy, or for oral use for Clos- New insights into the pharmacodynamic principles tridium difficile enterocolitis. The major concern is governing the activity of ceftazidime have led to a that the vancomycin-resistance gene is transmitted single daily-dose regimen, which has the advantage to staphylococcal strains, creating an issue of major of ease of use by patient and staff, both in hospital epidemiological importance. While a great deal of con- cern has been raised about vancomycin, it is still an If gentamicin, tobramycin, or netilmycin are used, important antimicrobial option. Indeed, it is recom- they are dosed at 0.6 mg/kg body weight in only 1 ex- mended for use in methicillin-resistant S. aureus change per day. Amikacin is dosed at 2.0 mg/kg body (MRSA) infections and in treatment of infections due weight, also in only 1 exchange per day (Table 2).
to beta-lactam-resistant organisms, as well as in treat- Gram Stain Reveals Yeast: If yeast is seen on Gram ment for infections in patients that have serious gram- stain, prompt initiation of antifungal therapy should positive infections and that are allergic to other be initiated. Although the mainstay of therapy in the agents, and in the treatment of C. difficile enterocoli- past has been amphotericin B, its toxicity has fre- tis that does not respond to metronidazole.
quently precluded its effective use. Experience with the newer imidazoles/triazoles and flucytosine sug- gest that these agents are well tolerated and positive bacteria, a gram-negative organism, or is CULTURE AND SENSITIVITY RESULTS ARE KNOWN ganisms, empiric therapy is indicated (Table 2). To prevent routine use of vancomycin and thus prevent Gram-Positive Micro-Organisms Cultured: Within emergence of resistant organisms, it is recommended 24 – 48 hours after the appropriate culture of dialy- that a first-generation cephalosporin, for example, sate fluid, 70% – 90% of these samples yield a spe- cefazolin or cephalothin (1 g daily in the long dwell), cific micro-organism (Table 4). If the organism is an in combination with ceftazidime be initiated. These enterococcus, the first-generation cephalosporin antibiotics can be mixed in the same dialysate bag as (cephalothin or cefazolin) and ceftazidime are replaced either loading or maintenance doses, without signifi- with ampicillin, 125 mg/L in each exchange; another cant loss of bioactivity. The dose for ceftazidime is 1.0 g antibiotic such as an aminoglycoside may be added, if necessary, based on sensitivity. A factor to consider A single antibiotic for initial treatment needs to in deciding whether or not to continue the amino- satisfy several criteria, including good antibacterial glycoside is the recognition that a high ampicillin level efficacy for coagulase-negative staphylococcus, will be achieved at the site of infection using this S. aureus, gram-negative Enterobacteriaceae, and rea- sonable efficacy for pseudomonas. In addition, it needs As previously discussed, we urge restraint in im- to have a reasonable half-life for once-per-day therapy mediately utilizing vancomycin for enterococci with- and clinically proven efficacy. The 1996 Recommen- out considering all the implications. Since enterococci dations involved the use of a combination of a first- are frequently derived from the gastrointestinal tract, generation cephalosporin and an aminoglycoside. The intra-abdominal pathology must be considered. More- need to avoid routine use of aminoglycoside arises over, care should be exercised in evaluating the di- from the concern to preserve residual renal function, alysate culture since other more fastidious and Antibiotic Dosing Recommendations for CAPD (Only) Patients With and Without Residual Renal Functiona CAPD continuous dosing (per liter exchange) LD 320/1600 mg p.o., MD 80/400 mg p.o.
MD = maintenance dose; LD = loading dose; ND = no data; p.o. = oral; q.i.d. = four times per day; IV = intravenous; q.d. = once per day;b.i.d. = twice per day; IP = intraperitoneally; NA = not applicable.
CAPD patients with residual renal function may require increased doses or more frequent dosing, especially when using intermittentregimens. For penicillins: “No change” is for those predominantly hepatically metabolized, or hepatically metabolized and renally excreted;“ND” means no data, but these are predominantly renally excreted, therefore probably an increase in dose by 25% is warranted; “NA” = notapplicable, that is, drug is extensively metabolized and therefore there should be no difference in dosing between anuric and nonanuricpatients. Anuric = <100 mL urine/24 hours; nonanuric = >100 mL/24 hours. These data for CAPD only.
a The route of administration is IP unless otherwise specified. The pharmacokinetic data and proposed dosage regimens presented here are based on published literature reviewed through January 2000, or established clinical practice. There is no evidence that mixingdifferent antibiotics in dialysis fluid (except for aminoglycosides and penicillins) is deleterious to the drugs or patients. Do not use thesame syringe to mix antibiotics.
b This is in each bag × 7 days, then in 2 bags/day × 7 days, and then in 1 bag/day × 7 days.
Treatment Strategies After Identification of Gram-Positive Organism on Culture If VRE, consider quinupristin/dalfopristin If no improvement, reculture and evaluate for exit-site or tunnel infection, catheter colonization, etc.
Choice of final therapy should always be guided by antibiotic sensitivities.
VRE = vancomycin-resistant enterococcus; MRSA = methicillin-resistant S. aureus; MRSE = methicillin-resistant slow-growing organisms from the bowel may be ing to therapy, consideration should be given to use present in conjunction with the enterococci.
of clindamycin or vancomycin. Also, if clear improve- If the organism is S. aureus, the first decision is ment is not observed within 48 hours, or if the cur- based on its sensitivity to methicillin. If it is sensitive rent peritonitis episode is a recurrence or a relapse, to methicillin, the first-generation cephalosporin is switching to an alternative agent such as clindamycin continued and the ceftazidime should be discontinued.
Since 24 – 48 hours will have elapsed since initia- Cultures Negative: Occasionally (less than 20%), tion of therapy, the clinician can judge whether the cultures may be negative for a variety of technical or empiric regimen is working. If the clinical response clinical reasons. Experience would indicate that, if the is less than desired, rifampin 600 mg/day orally (in patient is clinically improving, the first-generation single or split dose) can be added to the IP-adminis- cephalosporin should be continued and the tered first-generation cephalosporin. If there is MRSA, ceftazidime discontinued (Table 5). Duration of rifampin should be added as above, and the first-gen- therapy should be 2 weeks. If, on the other hand, no eration cephalosporin should be changed to clinical improvement occurs within 96 hours, repeat clindamycin or vancomycin. Vancomycin may be ad- evaluation is mandatory with consideration of myco- ministered 2 g (30 mg/kg body weight) IP every bacteria or fungi, and catheter replacement or removal 7 days. This dose should be modified for smaller indi- viduals and reflect a dose based on body weight. More- Gram-Negative Micro-Organisms Cultured: If a over, in the presence of residual renal function single ceftazidime-sensitive gram-negative organism, (> 500 mL/day urine output) a dosing interval of every such as Escherichia coli, klebsiella, or proteus is iso- 5 days is appropriate. Teicoplanin, where available, lated, this antibiotic is continued and first-genera- can be used in a dose of 15 mg/kg body weight every tion cephalosporin stopped (Table 6). Utilization of ceftazidime must be guided by in vitro sensitivity test- If the organism is identified as a gram-positive ing. If the culture report reveals multiple gram-nega- organism other than enterococcus or S. aureus, ceft- tive organisms, it is imperative to consider the azidime should be discontinued. Staphylococcus possibility of intra-abdominal pathology, necessitat- epidermidis is the most frequently identified organ- ism in this situation. Peritonitis caused by coagulase- In addition, if anaerobic bacteria are isolated, ei- negative staphylococci that are “resistant” to ther alone or in combination with other gram-nega- first-generation cephalosporin may not resolve. How- tive organisms, serious consideration should be given ever, if there is a clear response to empiric therapy to surgical intervention because of the likelihood of (cefazolin or cephalothin), continued therapy with bowel perforation. In this setting, metronidazole, in either antibiotic alone is appropriate. In this setting combination with ceftazidime or an aminoglycoside of methicillin-resistant S. epidermidis not respond- in the recommended doses, is the therapy of choice.
Treatment Strategies if Peritoneal Dialysis Fluid Cultures Are Negative at 24 to 48 Hours or Not Performed Discontinue ceftazidime or aminoglycoside Repeat cell count, Gram stain, and culture If culture positive, adjust therapy accordingly If culture negative, continue antibiotics, consider infrequent pathogens and/or catheter removal Treatment Recommendations if a Gram-Negative Organism Is Identified on Culture at 24 to 48 hours < 100 mL urine, aminoglycoside (see Empiric Therapy, Table 2) > 100 mL urine, ciprofloxacin 500 mg, p.o. b.i.d.
or sulfamethoxazole/trimethoprim 1–2 DS/day or aztreonam load 1 g/L; maintenance dose 250 mg/L IP/bag Continue cefazolin and ceftazidime and add metronidazole, 500 mg q.8 hours, p.o., IV, or rectally If no change in clinical status, consider surgical intervention IV = intravenously; DS = double strength; IP = intraperitoneally.
Metronidazole is administered IV, orally, or rectally, (Table 6). Infection with this organism type is gener- ally not as severe as with pseudomonas, and is usually Should the isolate be a pseudomonad (e.g., Pseudo- not associated with an ESI. Therapy for pseudomonas/ monas aeruginosa), ceftazidime is continued. Also, an stenotrophomonas peritonitis is recommended for agent with activity against the isolated organism de- 3 – 4 weeks if the patient is clinically improving. The termined by in vitro sensitivity testing should be consequences of persistent gram-negative peritonitis, added. Piperacillin, ciprofloxacin (see Treatment of particularly pseudomonas, on peritoneal membrane in- Exit-Site Infections, below), aztreonam, an amino- tegrity over the long term are poorly understood. How- glycoside, or sulfamethoxazole/trimethoprim are pos- ever, it is thought that it could lead to loss of peritoneal sible candidates to combine with the ceftazidime transport function. Therefore, consideration of early (Table 6). At least two antibiotics with activity against catheter removal is important to preserve peritoneal pseudomonads will be necessary for cure. Should function and to avoid repeated long-term treatment piperacillin be preferred, its dose is 4 g every 12 hours IV in adults. This dose is also appropriate for APD Antibiotic Toxicities: The intermittent dosing rec- patients. Pseudomonal peritonitis is extremely diffi- ommendation for aminoglycosides (amikacin, tobra- cult to cure, particularly when it develops as the con- mycin, gentamicin, and netilmycin) may reduce the sequence of a catheter-related infection. These risk of ototoxicity and cochlear toxicity. However, some organisms are known to protect themselves with a risk for such toxicity will remain, especially if treat- biofilm that makes effective antimicrobial penetra- ment courses are extended beyond 2 – 3 weeks, or tion difficult. Thus, in the setting of catheter-related when repeated courses, for example, for relapsing infection with these organisms, antibiotic treatment peritonitis, are given. Thus, prolonged treatment with without catheter removal has a low likelihood of thera- these agents should be limited to the rare occasion when no alternative, less toxic agents are likely to be The isolation of a Stenotrophomonas species, while infrequent, requires special attention since they dis- In intermittent dosing, dialysate and serum con- play sensitivity only to a few antimicrobial agents centrations depend on residual renal function. In pa- In many centers, during peritonitis, APD patients are changed to a CAPD schedule because it is then easier to evaluate the clinical course using standard- underdosing. Monitoring of aminoglycoside serum ized procedures for obtaining dialysate for cell count concentrations in CAPD peritonitisis may be per- and culture and sensitivity. Furthermore, the recom- formed routinely for similar reasons.
mendations for antibiotic treatment are based mainly Fungal Organisms Cultured: Many clinicians still on data obtained using CAPD and limited experience feel that catheter removal is indicated immediately in APD (Manley et al., 2000, J Am Soc Nephrol ).
after fungi are identified by Gram stain or culture.
If patients stay on APD, antibiotics can be given As indicated above (in the section, Gram Stain Re- continuously or intermittently (See Table 8). Because veals Yeast), recent experience with the newer imi- the bactericidal action of aminoglycosides is dose- dazoles/triazoles and flucytosine (orally or, if available, dependent, once-daily administration of amino- IP) suggest that these agents may also be efficaciously glycosides is recommended. Vancomycin and other administered (Table 7). Although prospective clinical glycopeptides can be given intermittently because of trials of PD-related fungal peritonitis comparing their unique pharmacokinetic properties. With all amphotericin B to the imidazole/triazoles–flucytosine other antibiotics, the dose in APD can only be extrapo- combinations have not been performed, a retrospec- lated from pharmacokinetic studies in CAPD, as no tive analysis of published data suggests this latter such studies are available in APD patients. Only one combination is as efficacious as amphotericin B, par- study on the clinical outcome of peritonitis in APD ticularly for nonfilamentous fungi. However, emer- patients has been published. In this study, the results gence of resistance to the imidazoles has occurred, of once-daily IP cefazolin and oral ciprofloxacin as thus raising some concerns. Where available, fungal empiric therapy were considered suboptimal (Troidle sensitivities should be obtained. It is reasonable that et al., 1999). Attention should be given to an adequate successful therapy should be continued for 4 – 6 weeks dwell time of at least 4 hours to allow absorption of (Table 7); however, if clinical improvement does not occur after 4 – 7 days of therapy, the catheter should An interesting option for treatment of peritonitis be removed. Therapy with these agents should be con- in APD patients is oral administration of antibiotics.
tinued, after catheter removal, orally with flucytosine However, here also pharmacokinetic studies are lack- and fluconazole daily for an additional 10 days ing and this route of administration can therefore only (Table 7). Oral flucytosine has been withdrawn from be recommended in uncomplicated episodes due to some markets (e.g., in Canada) and this will influ- As with CAPD, adjustments for APD prescription may be needed in patients who experience altered ultrafiltration during episodes of peritonitis.
clinical improvement. Occasionally, symptoms may persist beyond 48 – 96 hours. At 96 hours, if patients have not shown definitive clinical improvement, a re- Treatment Recommendations if Yeast or Other Fungus Identified on Gram Stain or Culture Loading dose 2 g p.o.; maintenance dose 1 g p.o.
200 mg, p.o., or intraperitoneally, daily If organism is resistant, consider itraconozole If clinical improvement, duration of therapy 4–6 weeks If no clinical improvement, remove catheter and continue therapy for 7 days after catheter removal Dosing of Antibiotics, by IP Intermittent Route, in Automated PD (These data for APD only) 20 mg/kg q.d., in first or second ambulatory dwell Maintenance dose 0.5 mg/kg q.d., in first or second ambulatory dwell.
IP = intraperitoneal; PD = peritoneal dialysis; IV = intravenous; b.i.d. = two times daily; q.d. = every day.
Unless otherwise specified, IP doses to be added to the 1st ambulatory dwell after the automated exchanges.
a Unpublished data.
b J Am Soc Nephrol 2000; 11:1310–16.
evaluation is essential. Specifically, cell counts, Gram is warranted and IV antibiotics should be continued stain, and cultures should be repeated. Antibiotic re- for 5 –7 days. In those patients with anaerobic bacte- moval techniques may be used in an attempt to maxi- ria or gram-negative organisms, exclusive of pseudomonas, the possibility of an intra-abdominal Among the paramount clinical concerns in patients process necessitating surgical exploration should be with persistent symptomatology is the presence of considered. Finally, if pseudomonas has been identi- intra-abdominal or gynecological pathology requiring fied and, the patient has failed to demonstrate any surgical intervention, or the presence of unusual or- significant clinical improvement within 48 – 72 hours ganisms, such as mycobacteria, fungi, or fastidious after initiating therapy, the catheter should be re- organisms. Identification of these latter organisms moved. As described above, two antibiotics with will often require special culture techniques and must antipseudomonal activity should be continued IV for be coordinated with the microbiology laboratory.
at least 5 – 7 days. The suggested duration of antibi- In patients with S. aureus infections that have not otic therapy after removal of the catheter may be shown significant improvement, the possibility of an modified, depending upon the clinical course. There underlying tunnel infection or an intra-abdominal are no studies establishing the appropriate duration abscess must be considered. Ultrasonography, or pos- of antimicrobial therapy following catheter removal.
sibly computed tomography, may be performed to as- If therapy for fungal peritonitis was initially insti- sess the presence of an occult abscess. In addition, in tuted but no clinical improvement has been seen, the the re-evaluation of the patient’s medical status, the catheter should be removed. Finally, for those patients antimicrobial regimen should be reassessed. Patients in whom the original cultures were negative, and who with S. aureus peritonitis treated with a first-genera- are still demonstrating persistence of symptomatol- tion cephalosporin to which rifampin has already been ogy at 96 hours, the catheter should be removed and added, and that demonstrate failure to clinically im- cultured, and IV antifungal agents should be contin- prove, should be re-evaluated. Specifically, evaluation for an occult tunnel infection should be considered. If a coagulase-negative staphylococcus (S. epidermidis) has been cultured from the dialysate effluent, and the patient has failed to respond to the initial therapy, rifampin may also be added in the doses recom- mended. Alternatively, in the setting of methacillin- resistant staphylococcus, vancomycin should be used.
If anaerobic bacteria have been identified by cul- ture, and the patient has not improved clinically by 96 hours, the catheter should be removed, surgical antibiotic regimen has been made, an additional exploration considered, the antibiotic regimen re- 72 hours will be needed to assess clinical response.
evaluated, and therapy should be continued IV for Patients Demonstrating Clinical Improvement: In 5 –7 additional days after catheter removal. Similarly, patients with gram-positive peritonitis and in patients if more than one gram-negative organism, other than with culture-negative peritonitis, antibiotic treatment pseudomonas, has been identified, catheter removal should be continued for at least 1 week after a clear (< 100 leukocytes/mm3) and negative cul- (DNA) fingerprinting with restriction-fragment- tures have been obtained. This means that 10 – length polymorphism and analysis. Re-infection from 14 days are usually adequate for treatment of perito- a pulmonary source should be considered in high- nitis in uncomplicated episodes due to coagulase-nega- risk populations. Most TB patients present with fe- tive staphylococci. In patients with S. aureus ver and abdominal pain. Peritoneal fluid differential peritonitis, the infection is usually more severe than leukocyte count, and radionucleotide imaging meth- in other gram-positive episodes. Therefore, a 3-week ods are not usually helpful in the differential diag- treatment is recommended for these episodes.
nosis of this entity. Smears of the peritoneal effluent In patients with an uncomplicated peritonitis epi- often fail to reveal acid-fast bacilli, thus diagnosis sode due to a single gram-negative micro-organism, must rely on TB cultures. Since peritoneal fluid cul- treatment with an effective antibiotic agent for about ture for acid-fast organisms usually takes 6 weeks, 21 days is usually adequate. Therapy for pseudomo- the diagnosis is frequently delayed in the majority nas/stenotrophomonas should be at least 21 days in of patients. In order to make an earlier diagnosis in patients not responding to therapy, invasive proce- In patients with multiple gram-negative micro- dures such as exploratory laparotomy or laparoscopy organisms, a high relapse-rate is common even with with biopsy of the peritoneum or omentum should adequate antibiotic therapy. Therefore, even in epi- be considered. Detection of mycobacterial DNA am- sodes with initial clinical improvement, removal of plified by polymerase chain reaction techniques from the catheter should be considered. If the catheter is peritoneal effluent hold the greatest promise for not removed, antibiotic treatment should be contin- rapid detection of TB. Recently, non-TB mycobacte- ued for at least 21 days. Computed tomography should ria have been associated with clinical peritonitis; be considered in order to detect possible abscess M. fortuitum, M. kansasii, and M. gordonae have been isolated from infected patients. In some episodes Fungal peritonitis can be treated with appropri- of sterile peritonitis, the use of molecular techniques ate antibiotics. This applies especially to Candida is necessary to identify mycobacterium as the caus- species. If successful, treatment should be continued Few data exist for the optimal choice and dura- Patients Failing to Demonstrate Clinical Improve- tion of chemotherapy of TB peritonitis. Based on the ment: In patients who fail to demonstrate clinical usual conservative approach to extrapulmonary TB, improvement, daily clinical judgment is of vital im- most reported cases have been treated with three portance. In those patients with persistent symptoma- drugs (isoniazid 300 mg orally, four times daily; tology during appropriate antibiotic treatment, one rifampicin 600 mg orally, four times daily; and pyrazi- should remove the catheter. Antibiotic treatment namide 1.5 g orally, four times daily), usually for should be continued for at least 1 week after catheter 12 months (Table 3). Pyridoxine (100 mg/day orally) removal. In patients with peritonitis due to multiple should be routinely ordered. Since streptomycin, even organisms and/or anaerobes, not only catheter re- in reduced doses, may cause ototoxicity after pro- moval but also an exploratory surgical intervention longed use, it should not be administered to the end- should be considered. If, after removal of the cath- stage renal disease patient. Similarly, ethambutol is eter, clinical improvement does not occur, an intra- not recommended because of the high risk of optic abdominal abscess should be considered.
neuritis. Catheter removal appears to be necessary term prophylactic use of penicillins or cephalospor- ins has not been shown to decrease the risk of peritonitis. In patients with chronic ESI, there are no tients with peritonitis that is not responding to data to show whether long-term antibiotic therapy appropriate antibiotic treatment, whether it is a cul- for chronic ESI is preferable to replacing the cath- ture-negative peritonitis, so-called sterile peritoni- eter. However, the regular use of intranasal or exit- tis, or proven bacterial peritonitis. In general, TB site mupirocin decreases the risk of S. aureus ESI (see peritonitis is due to reactivation of a latent focus section below). Data on the effectiveness of oral pro- rather than a primary infection through the cath- phylaxis with nystatin (3 × 500 IU) during antibiotic eter. However, in cases of prior pulmonary TB, re- therapy to decrease the risk of fungal peritonitis are infection can be confirmed by deoxyribonucleic acid Short-Term Antibiotic Prophylaxis: Invasive pro- cedures associated with transient bacteremia may infrequently cause peritonitis in PD patients. There- fore, a single dose of amoxicillin (2 g) before exten- age with or without erythema of the skin at the sive dental procedures is reasonable. Patients catheter–epidermal interface. A culture of the puru- undergoing colonoscopy with polypectomy are at risk lent drainage should be obtained (Figure 1). Empiric for enteric peritonitis, presumably from movement of antibiotic therapy may be initiated immediately if the bacteria across the bowel wall and into the perito- clinical appearance warrants early intervention, or neal cavity. Ampicillin plus an aminoglycoside, with delayed until the results of the culture are available.
or without metronidazole, given just prior to the pro- Gram-positive organisms are treated with an oral cedure may decrease the risk of peritonitis. The ab- penicillinase-resistant penicillin, cephalexin, or domen should be emptied of fluid prior to all sulfamethoxazole trimethoprim (see Flanigan et al., procedures involving the abdomen or pelvis (such as 1994). To prevent unnecessary exposure to vancomy- colonoscopy, renal transplantation, or endometrial cin, and thus emergence of resistant organisms, van- comycin should be avoided in the routine treatment Prophylactic Antibiotics and Catheter Placement: of gram-positive ESI and tunnel infections. In slowly- Prophylactic antibiotics given before catheter place- resolving or particularly severe-appearing S. aureus ment decrease the risk of subsequent infection. A first- ESI, add rifampin 300 mg two times daily. Gram-nega- generation cephalosporin has been most frequently tive organisms may be treated with oral quinolones used in this context. Routine use of vancomycin should such as ciprofloxacin 500 mg two times daily. Chela- tion interactions may occur between fluoroquinolones Use of Prophylactic Antibiotics After a Technique and concomitantly administered multivalent cations.
Break: Although there are no data on the use of pro- Calcium salts, oral iron supplements, zinc prepara- phylactic antibiotics after a known break in technique, tions, sucralfate, magnesium–aluminum antacids, and most nephrologists give a 1- to 2-day course of antibi- milk may reduce oral ciprofloxacin absorption by otics. A first-generation cephalosporin is probably 75% – 91%, with a possible significant reduction in adequate. Vancomycin use as prophylaxis in this set- antimicrobial activity. It is suggested that adminis- ting should be avoided, unless the patient is a known tration of the preparations be staggered as much as carrier of MRSA or has had some recent antecedent possible. A minimum spacing of 2 hours between event making MRSA more of a concern.
preparations is recommended, with the ciprofloxacin Exit-Site Infections and Prophylactic Antibiotics: administered first (see Lomaestro and Bailie, 1995).
Staphylococcus aureus nasal carriage is associated If the organism is P. aeruginosa and resolution is slow with an increased risk of S. aureus ESI, tunnel infec- or there is recurrence, IP ceftazidime may be added.
tions, peritonitis, and catheter loss. Diabetic patients Therapy should be continued until the exit site ap- and those on immunosuppressive therapy are also at pears completely normal. Prolonged antibiotics may increased risk for S. aureus catheter infections. Pro- be necessary. If 3 – 4 weeks of antibiotics fails to re- phylaxis with intranasal mupirocin, exit-site solve the infection, the catheter may be replaced.
mupirocin, or oral rifampin is effective in reducing Alternatively, revision of the tunnel may be performed S. aureus ESI (see Zimmerman et al., 1991; Bernar- in conjunction with continued antibiotic therapy. This dini et al., 1996). A small amount of mupirocin oint- procedure, however, may result in peritonitis, in which ment applied daily to the exit site, using a cotton swab, case the catheter should be promptly removed.
after routine exit-site care is as effective as oral Pericatheter erythema without purulent drainage rifampin in reducing ESI rates. Mupirocin is preferred is sometimes an early indication of infection. If the to rifampin for prophylaxis because toxicity from clinician suspects infection, then therapy should be mupirocin is negligible. The use of mupirocin oint- initiated, which may be either intensified local care, a ment at the exit site, however, should be avoided in local antibiotic ointment, or an oral antibiotic that cov- patients with polyurethane catheters (Cruz catheter) ers gram-positive organisms. An alternative approach as structural damage to the catheter has been re- is careful observation for additional signs of infection.
ported. Data on the use of cream at the exit site of polyurethane catheters are not available. All patients at an increased risk for S. aureus infections, includ- ing S. aureus carriers, diabetics, and immunocompro- mised patients, should be provided with prophylaxis.
A practical approach is to prescribe exit-site mupirocin for all such PD patients, thus eliminating the need Figure 1 — Flow chart for diagnosis and management of exit-site infections is shown.
signs and symptoms similar to those described in eter is not known. Empirically, a minimum of 3 weeks patients with sporadic peritonitis. Relapsing infec- between catheter removal and reinsertion of a new tions with coagulase-positive or -negative staphylo- catheter is recommended. However, removal of the cocci should be treated with cephalosporins and old catheter and insertion of a new one during the rifampin for approximately 4 weeks. However, in the same operation has been done successfully in the set- setting of relapsing peritonitis with methicillin-resis- ting of refractory tunnel infections as well as relaps- tant S. aureus or S. epidermidis, clindamycin or van- ing peritonitis (see Swartz et al., 1991). This comycin should be considered for therapy. In the simultaneous procedure may be recommended when presence of coagulase-positive staphylococcus infec- the relapsing peritonitis is due to either biofilm for- tion, a search for an occult tunnel infection should mation on the intra-abdominal section of the cath- also be made. If enterococci are recultured, ampicil- eter (predominately relapsing peritonitis due to lin and an aminoglycoside should be used in the rec- coagulase-negative staphylococcus), or to tunnel in- ommended doses. Consideration should also be given volvement (primarily relapsing peritonitis due to to the possibility of an intra-abdominal abscess. If no S. aureus). This approach should be limited to those clinical response is noted after 96 hours of therapy episodes in which the effluent WBC count has fallen for relapsing peritonitis, catheter removal is indicated.
to less than 100/µL with antibiotic therapy. Simulta- If the patient responds clinically, but subsequently neous catheter replacement should not be used for relapses an additional time, catheter removal and re- peritonitis episodes due to pseudomonas, fungus, or mycobacterium, nor should it be used if the patient In relapsing peritonitis caused by gram-negative or- has an intra-abdominal abscess or a suspected in- ganisms, one should evaluate clinically for an intra-ab- tra-abdominal source for the peritonitis (Swartz and dominal abscess. Catheter removal and surgical Messana, 1999). Since a PD-free interval (with or exploration should be strongly considered in these pa- without a catheter in place) may also be helpful in tients. Treatment with ceftazidime or an aminoglycoside resolving peritonitis, the timing of catheter reinser- alone can be used once culture results are known. If pseudomonas or stenotrophomonas organisms are iden- tified again on culture, the catheter should be removed.
USE OF ADJUNCTIVE THERAPY IN TREATMENT OF Finally, in those patients with relapsing peritonitis, short-term interruption of PD may be of value; however, the availability of supportive hemodialysis will dictate The performance of two to three rapid exchanges whether this option can be considered.
of PD solution immediately after diagnosis of perito- nitis is reported to be of symptomatic benefit, but does not appear to offer any other specific therapeutic ben- efits. A few rapid exchanges every 20 minutes is ad- vocated only for severe symptomatic peritonitis at the The optimal period of time between catheter re- start of therapy. Usual practice is the performance of moval for infection and reinsertion of a new cath- one rapid cleansing exchange prior to the longer dwell exchange with IP antibiotics. Heparin (500 – of recovery in APD patients and should be con- 1000 U/L) may be added to the regular regimen until sidered routine procedure whenever possible.
dialysate effluent clears. This usually occurs within Identification and sensitivity testing should be done as soon as possible to achieve rational anti- Thrombolytic therapy should be reserved for those infections in which no other cause or complication is Culture Procedure: The correct microbiological cul- evident, and should probably be limited to coagulase- ture of PD samples is of utmost importance to estab- negative staphylococcal or culture-negative infections.
lish the etiological agent and the appropriate Temporary discontinuation of PD with continuation antibiotic therapy. In addition, the type of organism of antibiotic therapy may be a reasonable adjunctive can indicate the possible source of infection. In the therapy for recurring, resistant, or relapsing infec- early days of CAPD, PD effluent was handled by labo- tions. Although the duration of this approach has not ratories as any other clinical specimen, that is, small been clearly established, durations of 7 – 28 days have amounts of fluid were cultured. Culture of large been advocated (see Pagniez et al., 1988; Locatelli amounts of fluid improves the accuracy of diagnosis et al., 1995). Variations of this approach have also been (See Sewell et al., 1990). Most methods presently proposed and include hyperconcentrated antibiotics employed incorporate either a concentration method, (antibiotic lock technique) or fibrinolytics added using filtration or centrifugation, or blood culture tech- within the catheter lumen at the time of peritoneal niques. The removal of antibiotics present in the speci- resting. Several small studies have reported some men may further improve the isolation rate. Some benefit using peritoneal rest with or without authors recommend lysis of peritoneal leukocytes to intracatheter agents, but only in cases of mildly symp- tomatic peritonitis. Overall, the role of thrombolytic Centrifugation of 50 mL of peritoneal effluent at therapy, as well as temporary discontinuation of PD, 3000g for 15 minutes, followed by resuspension of the is limited. Furthermore, pain, fever, and peritonitis- sediment in 3 – 5 mL of sterile saline, and inocula- like syndromes may be common with IP injection of tion of this material into a standard blood culture medium is usually adequate for primary isolation of In a recent report (including patients with associ- the causative organisms, although the inclusion of ated tunnel infections) evaluating the treatment of antibiotic neutralizing medium may be advantageous refractory and recurring peritonitis, simultaneous re- (see Alfa et al., 1997). The use of anaerobic blood cul- moval and replacement of the catheter was shown to ture media for inoculation is optional; some laborato- be beneficial to patients with refractory peritonitis (see Innes et al., 1994). It should be noted that the The speed with which bacteriological diagnosis can organisms involved in the failure of this approach in- be established is very important. Concentration meth- cluded mycobacteria, fungi, and/or pseudomonas. Si- ods not only facilitate correct microbial identification, multaneous catheter removal and replacement as an but also reduce the time necessary for bacteriological adjunctive therapy for peritonitis is described else- cultures. Rapid blood culture techniques (e.g., Bactec, Septi-Chek, BacT/Alert) may further speed up isola- tion and identification. The majority of cultures will become positive after the first 24 hours, and in over 75% of cases, diagnosis can be established in less than The routine collection of peripheral blood cultures rate microbiological diagnosis of peritonitis in APD is unnecessary in all but the youngest patients since patients, the following points are important: they are usually negative. If the patient appears to Cultures should be taken as early as possible from be septic or if an acute abdominal source is suspected suspected cases of peritonitis; the first cloudy fluid (appendicitis, cholecystitis, etc.), blood cultures may sample is the best specimen. A delay of several be helpful in identifying the source of infection. Occa- hours from the time of collection to the time of sionally, blood cultures yield gram-positive organisms culture does not seem to decrease the efficiency (α- or β-hemolytic streptococci), suggesting upper res- piratory tract infections or previous dental work.
Large volumes should be cultured or concentrated Frequency of Cultures: It is important to obtain the to maximize bacterial recovery rates.
first cloudy effluent for culture. The probability of Washing the specimen sediment with sterile sa- positive diagnostic culture is greatest from this speci- line or using antibiotic-removing or -neutralizing men. Patients should be instructed, therefore, to bring resin has been shown to improve the sensitivity the first cloudy fluid to the laboratory immediately.
Nonetheless, there is a continued need for scientifi- cally valid clinical trials in PD patients assessing al- ternative treatment strategies using newer and less atically. If cell counts are either rising or not toxic antibiotics. Inherent in this is the need to de- decreasing appropriately by 3 days, repeat cultures velop pharmacokinetic data in all PD modalities to should be taken and management guidelines should guide our use of these antibiotics. In this respect, the impact of residual renal function on dosing, as well “Sterile” or Culture-Negative Peritonitis: The inci- as the effect of antibiotics on residual renal function, dence of sterile peritonitis varies among units from is an important and fruitful area of research.
2% – 20%, depending on the methods used in the labo- An area of continued investigation must be related ratory. In this context, sterile peritonitis is manifested to the improvement of catheter technology and the by other clinical features of microbial peritonitis (e.g., early detection and therapy of catheter-related infec- evidence of inflammation and infection), and not just tions. Additional insights into catheter management turbid effluent dialysate. Occasionally, “sterile” peri- should be developed, particularly as they pertain to toneal fluid is reported by the laboratory when the exit and tunnel infections. The optimal interval be- causative organism is difficult to culture or inappro- fore catheter insertion can be performed safely must priate culture methods are used. This is typically the be defined, and improvement in catheter design and case when mycobacterial peritonitis or peritonitis due materials should be supported. The role of catheter to a rare fungus is present. Leading diagnostic symp- biofilm in PD infections also remains a potential area toms are persistently cloudy fluid, usually with rela- tively low cell counts, and lymphocytes or mononuclear cells predominant in the differential count. Possible A C K N O W L E D G M E N T S
causes of culture-negative peritonitis are listed below The authors thank Baxter Healthcare, Inc., McGaw Park, Illinois, which provided support for the meeting, and Salim Culture methods of low sensitivity are used. Many Mujais, MD, who helped with the meeting logistics. Special centers use laboratory facilities not experienced thanks to Deanna Gunderson, who coordinated all aspects in the specialized culture techniques recom- of manuscript preparation. In addition, the International Society for Peritoneal Dialysis has formally endorsed this Advisory Committee on Peritonitis Management and has established an official subcommittee of this organization Causative organism (e.g., mycobacteria) requires to address this important issue. In preparing this document, a bibliography of over 700 references has been established.
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